In the modern society, stresses that affect the cornea and conjunctiva increase, such as wearing contact lens, techno-stress, contact with allergies, air pollution, which associates with increasing patients suffering from dry eye. Patients suffering from dry eye tend to have lower corneal and conjunctival functions than normal to easily cause corneal epithelial disorder, corneal epithelial erosion, corneal ulcer, conjunctivitis, keratitis, eye infections, or the like.
Conventionally known methods for the prophylaxis or treatment of dry eye or eye diseases associated with reduced corneal and conjunctival functions include protecting the cornea and conjunctiva through administration of ophthalmic solution containing viscoelastic substances, such as chondroitin sulfate and hyaluronic acid, to impart water retention. The ophthalmic solution containing viscoelastic substances, however, may fail to provide a sufficient therapeutic effect because of insufficient protection for the cornea or conjunctiva. Therefore, there is a need for developing novel ophthalmic solution.
Ophthalmic solutions containing squalane have been recently reported to be effective for eye diseases such as dry eye. For example, the following ophthalmic solutions have been reported: an ophthalmic solution containing squalane is effective for the treatment of dry eye because it has an action to inhibit water evaporation (see Patent Document 1); an ophthalmic solution containing an oil, such as squalane, and a mucopolysaccharide is effective for the prophylaxis or improvement of dry eye associated with enhanced evaporation of tear fluid (see Patent Document 2); an ophthalmic solution containing squalane and vitamin E is effective for the treatment of inflammatory eye diseases (see Patent Document 3); and the like.
Since squalane thus has an activity to protect the cornea and the conjunctiva, the ophthalmic solution containing squalane are considered effective for the prophylaxis or treatment of dry eye as well as eye diseases associated with reduced corneal and conjunctival functions. Thus practical application of the ophthalmic solution containing squalane has been desired. Since squalane is oil and thus not compatible with water, ophthalmic solution containing squalane are typically designed as non-aqueous formulations, ophthalmic ointments, or emulsion formulations. Non-aqueous formulations and ophthalmic ointments, however, disadvantageously tend to cause pain at administration, blurred vision, stickiness, or others, which hinders continued use. Emulsion formulations containing squalane disadvantageously involve addition of a significant amount of surfactants to emulsify squalane, which causes irritations at administration or induces side effects. Furthermore, emulsion formulations containing squalane also disadvantageously require a large emulsifying device to be homogeneous an oil layer containing squalane in an aqueous layer in industrial manufacturing.
Patent Document 1 has reported a two-layer separation-type ophthalmic solution including two separate layers of an oil layer containing squalane and an aqueous layer, wherein the oil layer can be dispersed in the aqueous layer by shaking the ophthalmic solution before administration. Such a two-layer separation-type ophthalmic solution advantageously causes no reduction in comfort during use, unlike non-aqueous formulations nor ophthalmic ointments, because of the fact that the oil layer containing squalane is dispersed in the aqueous layer in the use of the ophthalmic solution, and further eliminates the need for a large amount of surfactants added or a large emulsifying device in manufacturing, unlike emulsion formulations. The two-layer separation-type ophthalmic solution containing squalane, however, may suffer from foaming by shaking before administration or a difficulty in achieving homogeneous dispersion of the oil layer in the aqueous layer only by shaking. The two-layer separation-type ophthalmic solution containing squalane may cause separation of the oil layer and the aqueous layer immediately after the oil layer is temporarily dispersed in the aqueous layer by shaking before administration, resulting in uneven concentration distribution of active ingredients, such as squalane, in the ophthalmic solution at administration. The ophthalmic solution with foaming or uneven dispersion thus fails to achieve homogeneous concentration of active ingredients, such as squalane, throughout the ophthalmic solution to cause uneven doses of active ingredients, which may inhibit achievement of expected prophylactic or therapeutic effects. Such problems have not been overcome by conventional techniques to hinder practical application of two-layer separation-type ophthalmic solution containing squalane.